Principles of surgery

PART I
Basic Considerations

CHAPTER 11
Transplantation

BASIC SCIENCE QUESTIONS

1. Class I HLA antigens are expressed on the membrane of

A. All nucleated cells

B. B lymphocytes

C. Monocytes

D. Dendritic cells

Answer: A

The main antigens involved in triggering rejection are coded for by a group of genes known as the major histocompatibility complex (MHC). These antigens, and hence genes, define the ‘foreign’ nature of one individual to another within the same species. In humans, the MHC complex is known as the human leukocyte antigen (HLA) system. It comprises a series of genes located on chromosome 6. The HLA antigens are grouped into two classes, which differ in their structure and cellular distribution. Class I molecules (named HLA-A, -B, and -C) are found on the membrane of all nucleated cells. Class II molecules (named HLA-DR, -DP, and -DQ) generally are expressed by antigen-presenting cells (APCs) such as B lymphocytes, monocytes, and dendritic cells. (See Schwartz 9th ed., p 274.)

2. Which of the following immunosuppressive drugs inhibits IL-2 synthesis?

A. Azathioprine

B. Mycophenolate mofetil

C. Tacrolimus

D. Sirolimus

Answer: C

Azathioprine inhibits DNA and RNA synthesis. Mycophenolate mofetil inhibits the synthesis of purine. Sirolimus inhibits lymphocyte function. (See Schwartz 9th ed., p 275, and Table 11-1.)

TABLE 11-1 Summary of the main immunosuppressive drugs

Image

3. Cyclosporine inhibits T-cell activation by

A. Directly binding to T-cell surface membrane

B. Increasing production of IL-2

C. Decreasing production of IL-10

D. Inhibiting calcineurin

Answer: D

Cyclosporine binds with its cytoplasmic receptor protein, cyclophilin, which subsequently inhibits the activity of calcineurin. Doing so impairs expression of several critical T-cell activation genes, the most important being for IL-2. As a result, T-cell activation is suppressed. (See Schwartz 9th ed., p 276.)

4. Which of the following is a component of the University of Wisconsin preservation solution?

A. Glucose

B. Magnesium

C. Raffinose

D. Albumin

Answer: C

The most commonly used fluid worldwide is the University of Wisconsin solution. It contains lactobionate, raffinose, and hydroxyethyl starch. Lactobionate is impermeable and prevents intracellular swelling; it also lowers the concentration of intracellular calcineurin and free iron, which may be beneficial in reducing reperfusion injury. Hydroxyethyl starch, a synthetic colloid, may help decrease hypothermia-induced cell swelling of endothelial cells and reduce interstitial edema. (See Schwartz 9th ed., p 282.)

CLINICAL QUESTIONS

1. The proportion of patients on the waiting list to patients transplanted is approximately

A. 1:1 (waiting:transplanted)

B. 1:3 (waiting:transplanted)

C. 3:1 (waiting:transplanted)

D. 8:1 (waiting:transplanted)

Answer: C

In 2005 (see Fig. 11-1), there were approximately 28,000 patients transplanted and 90,000 on the waiting list. (See Schwartz 9th ed., p 272.)

Image

FIG. 11-1. Patients on waiting list and number of organ transplants for 2005. (U.S. data from Organ Procurement and Transplantation Network/Scientific Registry of Transplant Recipients Annual Report, http://www.ustransplant.org). KP = kidney and pancreas.

2. Rejection that starts on postoperative day 2 is most likely

A. Hyperacute rejection

B. Accelerated acute rejection

C. Acute rejection

D. Chronic rejection

Answer: B

[Hyperacute] rejection, which usually occurs within minutes after the transplanted organ is reperfused, is due to the presence of preformed antibodies in the recipient, antibodies that are specific to the donor. These antibodies may be directed against the donor’s HLA antigens or they may be anti-ABO blood group antibodies.

[Accelerated acute] rejection, seen within the first few days posttransplant, involves both cellular and antibody-mediated injury. It is more common when a recipient has been sensitized by previous exposure to antigens present in the donor, resulting in an immunologic memory response.

Acute rejection usually is seen within days to a few months posttransplant. It is predominantly a cell-mediated process, with lymphocytes being the main cells involved.

[Chronic] rejection occurs months to years posttransplant. Now that short-term graft survival rates have improved so markedly, chronic rejection is an increasingly common problem. Histologically, the process is characterized by atrophy, fibrosis, and arteriosclerosis. Both immune and nonimmune mechanisms are likely involved. Clinically, graft function slowly deteriorates over months to years posttransplant. (See Schwartz 9th ed., p 274.)

3. The most significant side effect of sirolimus is

A. Nephrotoxicity

B. Thrombocytopenia

C. Glucose intolerance

D. Leukopenia

Answer: B

The major side effects of sirolimus include neutropenia, thrombocytopenia, and a significant elevation of the serum triglyceride and cholesterol levels. It also has been associated with impaired wound healing, leading to a higher incidence of wound-related complications. (See Schwartz 9th ed., pp 275-277, and Table 11-2.)

TABLE 11-2 Side effects and drug interactions of the main immunosuppressive drugs

Image

4. Cyclosporine levels may be decreased in patients who are also taking

A. Phenytoin

B. Erythromycin

C. Cimetidine

D. Fluconazole

Answer: A

The metabolism of cyclosporine is via the cytochrome P-450 system, therefore several drug interactions are possible. Inducers of P-450 such as phenytoin decrease blood levels; drugs such as erythromycin, cimetidine, ketoconazole, and fluconazole increase them. (See Schwartz 9th ed., p 276, and Table 11-2.)

5. Bowel removed from a living donor for small bowel transplant is most commonly

A. Proximal jejunum

B. Mid to distal jejunum

C. Proximal ileum

D. Mid to distal ileum

Answer: D

Living-donor intestinal transplants usually involve removal of about 200 cm of the donor’s ileum, with inflow and outflow provided by the ileocolic vessels. (See Schwartz 9th ed., p 282.)

6. Ischemia time of a harvested lung should ideally be less than

A. 6 hours

B. 12 hours

C. 24 hours

D. 36 hours

Answer: A

With kidneys, cold ischemic times should be kept below 36 to 40 hours; after that, delayed graft function significantly increases. With pancreata, more than 24 hours of ischemia increases problems due to pancreatitis and duodenal leaks. With livers, more than 16 hours of ischemia increases the risk for primary nonfunction and biliary complications. Hearts and lungs tolerate preservation poorly; ideally, ischemia times should be below 6 hours. With marginal donors, all of these times should be adjusted further downward. (See Schwartz 9th ed., p 282.)

7. The most appropriate treatment of a lymphocele following renal transplantation is

A. Observation until resolution

B. Percutaneous aspiration

C. Laparoscopic or open peritoneal window

D. Open exploration with sclerotherapy

Answer: C

The reported incidence of lymphoceles (fluid collections of lymph that generally result from cut lymphatic vessels in the recipient) is 0.6 to 18%. Lymphoceles usually do not occur until at least 2 weeks posttransplant. Symptoms are generally related to the mass effect and compression of nearby structures (e.g., ureter, iliac vein, allograft renal artery), and patients develop hypertension, unilateral leg swelling on the side of the transplant, and elevated serum creatinine. Ultrasound is used to confirm a fluid collection, although percutaneous aspiration may be necessary to exclude presence of other collections such as urinomas, hematomas, or abscesses. The standard surgical treatment is creation of a peritoneal window to allow for drainage of the lymphatic fluid into the peritoneal cavity, where it can be absorbed. Either a laparoscopic or an open approach may be used. Another option is percutaneous insertion of a drainage catheter, with or without sclerotherapy; however, it is associated with some risk of recurrence or infection. (See Schwartz 9th ed., p 289.)

8. The major cause of death following renal transplantation is

A. Rejection with acute renal failure

B. Vascular (myocardial infarction or stroke)

C. Malignancy

D. Sepsis

Answer: B

The major cause of death in all kidney recipients is cardiovascular (myocardial infarction or stroke); sepsis accounts for less than 3%, while malignancy accounts for 2%. (See Schwartz 9th ed., p 290.)

9. The leading cause of graft loss following renal transplantation is

A. Recipient death

B. Acute rejection

C. Chronic nephropathy

D. Pyelonephritis

Answer: A

Currently, the most common cause of graft loss is recipient death (usually from cardiovascular causes) with a functioning graft. The second most common cause is chronic allograft nephropathy. Characterized by a slow, unrelenting deterioration of graft function, it likely has multiple causes (both immunologic and nonimmunologic). The graft failure rate due to surgical technique has remained at about 2%. (See Schwartz 9th ed., p 290.)

10. Back table preparation of a donor pancreas prior to transplantation includes

A. Removal of the donor duodenum

B. Removal of the tail of the pancreas with the spleen

C. Ligation of the proximal splenic vein

D. Placement of an arterial graft to connect the splenic and superior mesenteric arteries

Answer: D (See Schwartz 9th ed., p 292, and Fig. 11-2.)

Image

FIG. 11-2. Bench preparation of pancreas graft. Steps include (A) removal of the spleen; (B) removal of tissue along the superior and inferior aspect of the tail of the pancreas; (C) trimming of excess duodenum; and (D) ligation of vessels at the root of the mesentery and placement of arterial Y-graft.

11. The most common etiology of liver failure in patients undergoing liver transplantation is

A. Alcoholic cirrhosis

B. Metabolic disease

C. Chronic hepatitis

D. Fulminant (acute) liver failure

Answer: C

Chronic liver diseases account for the majority of liver transplants today. The most common cause in North America is chronic hepatitis, usually due to hepatitis C and less commonly to hepatitis B. Chronic alcohol abuse accelerates the process, especially with hepatitis C. Progression from chronic infection to cirrhosis is generally slow, usually occurring over a period of 10 to 20 years. Chronic hepatitis may also result from autoimmune causes, primarily in women. It can present either acutely over months or insidiously over years. Alcohol often plays a role in end-stage liver disease secondary to hepatitis C, but it may also lead to liver failure in the absence of viral infection. In fact, alcohol is the most common cause of end-stage liver disease in the United States. Such patients generally are suitable candidates for a transplant as long as an adequate period of sobriety can be documented. (See Schwartz 9th ed., p 295.)

12. Following biopsy which shows no vascular or lymphatic invasion, which of the following patients with hepatocellular carcinoma would be considered a candidate for liver transplantation?

A. A single tumor in the left lobe 5.5 cm in diameter

B. Two tumors, both in the right lobe, 3.5 cm and 2.5 cm in diameter

C. Three tumors, in the right and left lobes, 2.5 cm, 2.8 cm, and 1.0 cm in diameter

D. None of the above

Answer: C

Long-term patient survival in early series of OLT for HCC only reached 30 to 40%. It was not until patient selection strategies evolved that OLT became a more effective treatment. In a landmark 1996 study by Mazzaferro and colleagues at the University of Milan, characteristics of patients with HCC that were good candidates for OLT were described. These characteristics, now commonly referred to as the Milan criteria, included (a) a single lesion 5 cm or 1 to 3 tumors, each 3 cm; and (b) absence of vascular or lymphatic invasion. Patients meeting these criteria achieved an impressive 85% 4-year overall patient survival, while those patients that exceeded the Milan criteria had only 50% 4-year survival. (See Schwartz 9th ed., p 296.)

13. Which of the following is an indication for liver transplantation in a patient with acute liver failure?

A. INR >6.5

B. Age 40

C. Creatinine >2.0

D. Duration of jaundice >3 days prior to onset of encephalopathy

Answer: A

Acute liver disease, more commonly termed fulminant hepatic failure, is defined as the development of hepatic encephalopathy (HE) and profound coagulopathy shortly after the onset of symptoms, such as jaundice, in patients without pre-existing liver disease. The most common causes include acetaminophen overdose, acute hepatitis B infection, various drugs and hepatotoxins, and Wilson’s disease; often, however, no cause is identified. Treatment consists of appropriate critical care support, giving patients time for spontaneous recovery. The prognosis for spontaneous recovery depends on the patient’s age (those younger than 10 and older than 40 years have a poor prognosis), the underlying cause, and the severity of liver injury (as indicated by degree of HE, coagulopathy, and kidney dysfunction; Table 11-3). (See Schwartz 9th ed., p 296.)

TABLE 11-3 Indications for a liver transplant in patients with acute liver failure


Acetaminophen toxicity

pH 7.30

Prothrombin time >100 s (INR >6.5)

Serum creatinine >300 mmol/L (>3.4 mg/dL)

No acetaminophen toxicity

Prothrombin time >100 s (INR >6.5)

age 10 or >40 y

Non-A, non-B hepatitis

Duration of jaundice before onset of encephalopathy >7 d

Serum creatinine >300 mmol/L (>3.4 mg/dL)


INR = International Normalized Ratio.

14. Which of the following is one of the variables of the MELD score?

A. Creatinine

B. Age

C. Degree of encephalopathy

D. Cause of hepatic failure

Answer: A

Waiting list mortality can be quite accurately predicted in chronic liver failure patients by calculating their MELD (model for end-stage liver disease) score. The formula for calculation of this is:

MELD score = 3.8 × log (e) (bilirubin mg/dL) + 11.2 × log (e) (INR) + 9.6 log (e) (creatinine mg/dL)

A higher MELD score indicates a sicker patient, with a higher risk for mortality. In the United States, this scoring system has proven to be a useful method to determine the allocation of livers, with priority given to the sickest individuals. The calculated score does not take into account special situations such as HCC, which have a definite impact on waiting list mortality, but scoring exceptions are applied to these situations to allow for timely transplants. (See Schwartz 9th ed., p 297.)

15. The most common vascular complication after liver transplantation is

A. Hepatic vein thrombosis

B. Portal vein thrombosis

C. Hepatic artery thrombosis

D. Inferior vena cava thrombosis

Answer: C

The incidence of vascular complications after liver transplants ranges from 8 to 12%. Thrombosis is the most common early event, with stenosis and pseudoaneurysm formation occurring later. Hepatic artery thrombosis (HAT) has a reported incidence of about 3 to 5% in adults and about 5 to 10% in children. The incidence tends to be higher in partial liver transplant recipients. After HAT, liver recipients may be asymptomatic or may develop severe liver failure secondary to extensive necrosis. Doppler ultrasound evaluation is the initial investigative method of choice, with more than 90% sensitivity and specificity. If HAT is suggested by radiologic imaging, urgent re-exploration is indicated, with thrombectomy and revision of the anastomosis. If hepatic necrosis is extensive, a retransplant is indicated. However, HAT also may present in a less dramatic fashion. Thrombosis may render the common bile duct ischemic, resulting in a localized or diffuse bile leak from the anastomosis or in a more chronic, diffuse biliary stricture. (See Schwartz 9th ed., p 302.)

16. PTLD (posttransplant lymphoproliferative disorder) is caused by

A. Poorly controlled immunosuppression

B. Induction of lymphocyte antigens by immunosuppression

C. Cytomegalovirus infection

D. Epstein-Barr virus infection

Answer: D

Viral infections generally are not seen until after the first month posttransplant. CMV is the most common pathogen involved. Its presentation ranges from asymptomatic infection to tissue-invasive disease. Epstein-Barr virus (EBV), another member of the herpesvirus family, also may be seen posttransplant. A wide spectrum of clinical presentations is possible, including an asymptomatic rise in antibody titers, a mononucleosis syndrome, hepatitis, and posttransplant lymphoproliferative disorder (PTLD). The most severe form of infection, PTLD can present as a localized tumor of the lymph nodes or GI tract, or rarely as a rapidly progressive, diffuse, often fatal lymphomatous infiltration. (See Schwartz 9th ed., p 304.)

17. The most common indication for pediatric liver transplantation is

A. Wilson’s disease

B. Alagille’s syndrome

C. Biliary atresia

D. Tyrosinemia

Answer: C

Biliary atresia is the most common indication for a pediatric liver transplant. The incidence of biliary atresia is about one in 10,000 infant births. Other cholestatic disorders that may eventually require a transplant include sclerosing cholangitis, familial cholestasis syndromes, and paucity of intrahepatic bile ducts (as seen with Alagille syndrome). Metabolic disorders probably account for the next largest group of disorders that may require a liver transplant. Such disorders may directly result in liver failure or may have mainly extrahepatic manifestations. Alpha1-antitrypsin deficiency is the most common metabolic disorder that may require a liver transplant. Such patients may present with jaundice in the neonatal period, but this usually resolves. Subsequently, they may present in late childhood or early adolescence with cirrhosis and portal hypertension. Another metabolic disorder resulting in liver failure is tyrosinemia, a hereditary disorder characterized by deficiency of an enzyme that degrades the metabolic products of tyrosine, resulting in cirrhosis and a greatly increased risk for HCC. Still another is Wilson’s disease, an autosomal recessive disorder characterized by copper accumulation in the liver, central nervous system, kidneys, eyes, and other organs, that may present as fulminant, subfulminant, or chronic liver failure. (See Schwartz 9th ed., p 304.)

18. Following transplantation, patients are at increased risk for which of the following malignancies?

A. Melanoma

B. Kaposi’s sarcoma

C. Colon cancer

D. Follicular carcinoma of the thyroid

Answer: B

Transplant recipients are at increased risk for developing certain types of de novo malignancies, including nonmelanomatous skin cancers (three- to sevenfold increased risk), lymphoproliferative disease (two- to threefold increased risk), gynecologic and urologic cancers, and Kaposi’s sarcoma. The risk ranges from 1% among renal allograft recipients to approximately 5 to 6% among recipients of small bowel and multivisceral transplants. (See Schwartz 9th ed., p 309.)